Analysing impedance measurements

ABSTRACT

A method for use in analysing impedance measurements performed on a subject, the method including, in a processing system determining at least one impedance value indicative of the impedance of at least one leg segment of the subject; and determining an indicator using the at least one impedance value, the indicator being indicative of extracellular fluid levels in the at least one leg segment and being used in the assessment of venous insufficiency.

BACKGROUND OF THE INVENTION

The present invention relates to a method and apparatus for use inanalysing impedance measurements, and in particular, to a method andapparatus for determining an indicator indicative of extracellular fluidlevels using impedance measurements, the indicator being usable inidentifying venous insufficiency, lymphoedema and/or oedema.

DESCRIPTION OF THE PRIOR ART

The reference in this specification to any prior publication (orinformation derived from it), or to any matter which is known, is not,and should not be taken as an acknowledgment or admission or any form ofsuggestion that the prior publication (or information derived from it)or known matter forms part of the common general knowledge in the fieldof endeavour to which this specification relates.

Venous insufficiency is a condition characterized by an inability forveins to adequately return blood to the heart. Normally, when a subjectis in a standing position, the blood in the subject's leg veins is urgedback towards the heart against gravity by a combination of mechanisms,such as muscular squeezing of the leg veins, and through the action ofone-way valves in the veins. However, conditions can arise such asincreased pressure within the veins, deep vein thrombosis (DVT),phlebitis, or the like, which lead to blood pooling in the legs.

Chronic venous disease (CVD) is common with a 3-7% prevalence, resultingin an economic cost US $1 billion per annum.

Typical detection methods for venous insufficiency involve examining forphysical symptoms such as swelling in the leg or ankle, tightness in thecalves, leg tiredness, pain while walking, or the like. Venousinsufficiency may also be associated with varicose veins.

Other techniques for assessing venous insufficiency include measuringthe ambulatory venous pressure, which is achieved by inserting a needleinto the vein on the dorsum of the foot. Whilst this is regarded as thegold standard of haemodynamic investigation, this is invasive, and it istherefore desirable to find alternative non-invasive techniques. Twosuch methods are air plethysmography (APG) and strain gaugeplethysmography (SPG).

SPG involves placing mercury strain gauges in a silastic band around thecalf muscle which are calibrated to read percentage leg volume changes,as described for example in Nicolaides A N (2000) “Investigation ofChronic Venous Insufficiency: A Consensus Statement” Circulation102:126-163. These measurements are typically performed during exerciseregimens to allow venous refilling time and the ejection volume to beassessed. APG uses an air bladder which surrounds the leg from the kneeto the ankle. The bladder is inflated to a known pressure, with volumechanges in the calf muscle being determined based on changes in pressureon the bladder during a sequence of postural changes.

However, these techniques are only of limited accuracy, and can requireextensive calibration and exercise, to allow useable measurement to beobtained.

Lymphoedema is a condition characterised by excess protein and oedema inthe tissues as a result of reduced lymphatic transport capacity and/orreduced tissue proteolytic capacity in the presence of a normallymphatic load. Acquired, or secondary lymphoedema, is caused by damagedor blocked lymphatic vessels. The commonest inciting events are surgeryand/or radiotherapy. However, onset of lymphoedema is unpredictable andmay develop within days of its cause or at any time during a period ofmany years after that cause.

One existing technique for determining biological parameters relating toa subject, such as fluid levels, involves the use of bioelectricalimpedance. This involves measuring the electrical impedance of asubject's body using a series of electrodes placed on the skin surface.Changes in electrical impedance at the body's surface are used todetermine parameters, such as changes in fluid levels, associated withthe cardiac cycle or oedema.

US2006/0111652 describes methods for enhancing blood and lymph flow inthe extremities of a human. As part of this method, impedancemeasurements are used to assess segmental blood flows within the limbs.

US2005/0177062 describes a system for measuring the volume, compositionand the movement of electroconductive body fluids, based on theelectrical impedance of the body or a body segment. This is usedprimarily for electromechanocardiography (ELMEC) or impedancecardiography (IKG) measurements for determining hemodynamic parameters.

WO00/79255 describes a method of detection of oedema by measuringbioelectrical impedance at two different anatomical regions in the samesubject at a single low frequency alternating current. The twomeasurements are analysed to obtain an indication of the presence oftissue oedema by comparing with data obtained from a normal population.

SUMMARY OF THE PRESENT INVENTION

The present invention seeks to ameliorate one or more problems of theproblems associated with the prior art.

In a first broad form the present invention seeks to provide a methodfor use in analysing impedance measurements performed on a subject, themethod including, in a processing system:

-   -   a) determining at least one impedance value indicative of the        impedance of at least one leg segment of the subject;    -   b) determining an indicator using the at least one impedance        value, the indicator being indicative of extracellular fluid        levels in the at least leg segment and being used in the        assessment of venous insufficiency.

Typically the method includes, in a processing system:

-   -   a) comparing the indicator to a reference; and,    -   b) providing an indication of the results of the comparison to        allow determination of a presence, absence or degree of venous        insufficiency.

Typically the method includes, in a processing system:

-   -   a) determining a first indicator value with the subject in a        first orientation;    -   b) determining a second indicator value with the subject in a        second orientation; and,    -   c) determining an indicator change based on a difference between        the first and second fluid indicator values, the indicator        change being used in the assessment of venous insufficiency.

Typically the method includes, in the processing system:

-   -   a) comparing the indicator change to a reference; and,    -   b) providing an indication of the results of the comparison to        allow determination of a presence, absence or degree of venous        insufficiency.

Typically the method includes, in a processing system, determining anindex using the at least one impedance value, the index being indicativeof a ratio of extracellular to to intracellular fluid levels in the atleast leg segment, the index being used in the assessment of venousinsufficiency.

Typically the method includes, in the processing system:

-   -   a) comparing the index to a reference; and,    -   b) providing an indication of the results of the comparison to        allow determination of a presence, absence or degree of venous        insufficiency.

Typically the method includes, diagnosing the presence of venousinsufficiency if:

-   -   a) an indicator is less than first reference; and,    -   b) an index is greater than a second reference.

Typically the method includes, in a processing system:

-   -   a) determining a first index value with the subject in a first        orientation;    -   b) determining a second index value with the subject in a second        orientation; and,    -   c) determining an index change based on a difference between the        first and second fluid index values, the index change being used        in the assessment of venous insufficiency.

Typically the method includes, in the processing system:

-   -   a) determining a first indicator value with the subject in a        first orientation;    -   b) after positioning the subject in a second orientation for a        predetermined time period, determining a second indicator value        with the subject in the first orientation; and,    -   c) determining a difference between the first and second fluid        indicator values, the difference being used in the assessment of        venous insufficiency.

Typically the method includes, in the processing system:

-   -   a) monitoring the difference;    -   b) determining the time taken for the difference fall below a        reference; and,    -   c) providing an indication of the time taken to allow        determination of a presence, absence or degree of venous        insufficiency.

Typically the method includes, in a processing system:

-   -   a) determining a pre-treatment indicator value prior to        treatment of the subject;    -   b) determining a post-treatment indicator value following        treatment of the subject for venous insufficiency; and,    -   c) determining an indicator change based on a difference between        the pre-treatment and post-treatment indicator values, the        indicator change being used in the assessment of venous        insufficiency.

Typically the method includes, diagnosing the presence of venousinsufficiency if the indicator change is greater than a reference.

Typically the reference includes using a reference that is at least oneof:

-   -   a) an indicator or index determined for another limb of the        subject;    -   b) a reference determined from a sample population; and,    -   c) a previous indicator or index determined for the subject.

Typically the method includes, in the processing system, displaying atleast one of:

-   -   a) an indicator;    -   b) an index ratio;    -   c) an index;    -   d) an indicator change;    -   e) an index change;    -   f) one or more impedance parameter values; and,    -   g) results of a comparison.

Typically the first impedance is measured at a measurement frequency ofat least one of:

-   -   a) less than 100 kHz;    -   b) less than 50 kHz; and,    -   c) less than 10 kHz.

Typically the method includes, in the processing system, using the atleast one impedance measurement as an estimate of a resistance of thesubject at a zero measurement frequency.

Typically the method includes measuring at least one second impedancevalue, the at least one second impedance value being measured at ameasurement frequency of at least one of:

-   -   a) greater than 200 kHz;    -   b) greater than 500 kHz; and,    -   c) greater than 1000 kHz.

Typically the method includes, in the processing system, using the atleast one second impedance measurement as an estimate of a resistance ofthe subject at an infinite measurement frequency.

Typically the method includes, in the processing system:

-   -   a) determining a plurality of impedance values; and,    -   b) determining at least one impedance parameter value from the        plurality of impedance values.

Typically the impedance parameter values include at least one of

-   -   R₀ which is the resistance at zero frequency;    -   R_(∞) which is the resistance at infinite frequency; and,    -   Z_(c) which is the resistance at a characteristic frequency.

Typically the method includes, in the processing system:

-   -   a) determining values for impedance parameters R₀ and R_(∞) from        the measured impedance values; and,    -   b) calculating the index (I) using the equation:

$I = \frac{R_{\infty}}{R_{0} - R_{\infty}}$

Typically the method includes, in the processing system, determining theparameter values using the equation:

$Z = {R_{\infty} + \frac{R_{0} - R_{\infty}}{1 + \left( {{j\omega}\; \tau} \right)^{({1 - \alpha})}}}$

-   -   where:        -   Z is the measured impedance at angular frequency ω,        -   τ is a time constant, and        -   α has a value between 0 and 1.

Typically the method includes, in the computer system, causing theimpedance measurements to be performed.

Typically the method includes, in the computer system:

-   -   a) causing one or more electrical signals to be applied to the        subject using a first set of electrodes;    -   b) measuring electrical signals across a second set of        electrodes applied to the subject in response to the applied one        or more signals; and,    -   c) determining from the applied signals and the measured signals        at least one measured impedance value.

In a second broad form the present invention seeks to provide apparatusfor use in analysing impedance measurements performed on a subject, theapparatus including a processing system for:

-   -   a) determining at least one impedance value, indicative of the        impedance of at least leg segment of the subject;    -   b) determining an indicator using the at least one impedance        value, the indicator being indicative of extracellular fluid        levels in the at least leg segment and being used in the        assessment of venous insufficiency.

Typically the apparatus includes a processing system for:

-   -   a) causing one or more electrical signals to be applied to the        subject using a first set of electrodes;    -   b) measuring electrical signals across a second set of        electrodes applied to the subject in response to the applied one        or more signals; and,    -   c) determining from the applied signals and the measured signals        at least one measured impedance value.

Typically the apparatus includes:

-   -   a) a signal generator for generating electrical signals; and,    -   b) a sensor for sensing electrical signals.

In a third broad form the present invention seeks to provide a methodfor use in assessing the presence, absence or degree of venousinsufficiency, the method including, in a processing system:

-   -   a) determining at least one impedance value, indicative of the        impedance of at least leg segment of the subject; and,    -   b) determining an indicator using the at least one impedance        value, the indicator being indicative of extracellular fluid        levels in the at least leg segment and being used in the        assessment of venous insufficiency.

In a fourth broad form the present invention seeks to provide a methodfor use in analysing impedance measurements performed on a subject, themethod including, in a processing system:

-   -   a) determining at least one impedance value indicative of the        impedance of at least one body segment of the subject;    -   b) determining an indicator using at least one impedance value,        the indicator being indicative of extracellular fluid levels in        the at least one body segment;    -   c) determining an index using at least one impedance value, the        index being indicative of a ratio of extracellular to        intracellular fluid levels in the at least one body segment;    -   d) comparing the indicator to a first reference;    -   e) comparing the index to a second reference; and,    -   f) providing an indication of the results of the comparisons.

Typically the method includes, in the processing system, determining theindicator using an impedance measurement performed at a single lowfrequency.

Typically the at least one impedance measurement is measured at ameasurement frequency of at least one of:

-   -   a) less than 100 kHz;    -   b) less than 50 kHz; and,    -   c) less than 10 kHz.

Typically the method includes, in the processing system, using the atleast one impedance measurement as an estimate of a resistance of thesubject at a zero measurement frequency.

Typically the method includes measuring at least one second impedancevalue, the at least one second impedance value being measured at ameasurement frequency of at least one of:

-   -   a) greater than 200 kHz;    -   b) greater than 500 kHz; and,    -   c) greater than 1000 kHz.

Typically the method includes, in the processing system, using the atleast one second impedance measurement as an estimate of a resistance ofthe subject at an infinite measurement frequency.

Typically the method includes, in the processing system:

-   -   a) determining a plurality of impedance values; and,    -   b) determining at least one impedance parameter value from the        plurality of impedance values.

Typically the method includes, in the processing system:

-   -   a) at each of three frequencies, determining first and second        parameter values for first and second impedance parameters        relating to the impedance of at least one body segment of the        subject;    -   b) solving simultaneous equations representing a circle defined        with respect to the first and second impedance parameters to        thereby determine circle parameter values, the equations being        solved using the first and second parameter values at each of        the three frequencies;    -   c) using the circle parameter values to determine a third        impedance parameter value at a respective frequency; and,    -   d) using the third impedance parameter value to determine an        indicator indicative of relative fluid levels within the body        segment of the subject.

Typically the first and second parameter values are resistance andreactance values.

Typically the impedance parameter values include at least one of:

-   -   (1) R₀ which is the resistance at zero frequency;    -   (2) R_(∞) which is the resistance at infinite frequency; and,    -   (3) Z_(c) which is the resistance at a characteristic frequency.

Typically the method includes, in the processing system:

-   -   a) determining values for impedance parameters R₀ and R_(∞) from        the measured impedance values; and,    -   b) calculating the index (I) using the equation:

$I = \frac{R_{\infty}}{R_{0} - R_{\infty}}$

Typically the method includes, in the processing system, determining theparameter values using the equation:

$\begin{matrix}{Z = {R_{\infty} + \frac{R_{0} - R_{\infty}}{1 + ({j\omega\tau})^{({1 - \alpha})}}}} & (1)\end{matrix}$

-   -   (a) where:        -   1. Z is the measured impedance at angular frequency ω,        -   2. τ is a time constant, and        -   3. α has a value between 0 and 1.

In a fifth broad form the present invention seeks to provide apparatusfor use in analysing impedance measurements performed on a subject, theapparatus including a processing system for:

-   -   a) determining at least one impedance value indicative of the        impedance of at least one body segment of the subject;    -   b) determining an indicator using at least one impedance value,        the indicator being indicative of extracellular fluid levels in        the at least one body segment;    -   c) determining an index using at least one impedance value, the        index being indicative of a ratio of extracellular to        intracellular fluid levels in the at least one body segment;    -   d) comparing the indicator to a first reference;    -   e) comparing the index to a second reference; and,    -   f) providing an indication of the results of the comparisons.

Typically the processing system is for:

-   -   a) causing one or more electrical signals to be applied to the        subject using a first set of electrodes;    -   b) measuring electrical signals across a second set of        electrodes applied to the subject in response to the applied one        or more signals; and,    -   is c) determining from the applied signals and the measured        signals at least one measured impedance value.

Typically the apparatus includes:

-   -   a) a signal generator for generating electrical signals; and,    -   b) a sensor for sensing electrical signals.

In a sixth broad form the present invention seeks to provide a methodfor use in distinguishing the presence of oedema and lymphoedema in asubject, the method including, in a processing system:

-   -   a) determining at least one impedance value indicative of the        impedance of at least one body segment of the subject;    -   b) determining an indicator using at least one impedance value,        the indicator being indicative of extracellular fluid levels in        the at least one body segment;    -   c) determining an index using at least one impedance value, the        index being indicative of a ratio of extracellular to        intracellular fluid levels in the at least one body segment;    -   d) comparing the indicator to a first reference;    -   e) comparing the index to a second reference; and,    -   f) providing an indication of the results of the comparisons,        the results being used to distinguish oedema and lymphoedema.

It will be appreciated that the broad forms of the invention may be usedindividually or in combination, and may be used for assessing venousinsufficiency as well as diagnosing the presence, absence or degree of arange of conditions in addition to and including oedema, lymphodema,body composition, or the like.

BRIEF DESCRIPTION OF THE DRAWINGS

An example of the present invention will now be described with referenceto the accompanying drawings, in which:

FIG. 1 is a schematic diagram of a first example of impedance measuringapparatus;

FIG. 2 is a flowchart of an example of a process for use in analysingimpedance measurements;

FIG. 3 is a schematic diagram of a second example of impedance measuringapparatus;

FIG. 4 is a schematic diagram of an example of a computer system;

FIG. 5 is a flowchart of an example of a process for performingimpedance measurements;

FIG. 6A is a schematic of an example of a theoretical equivalent circuitfor biological tissue;

FIG. 6B is an example of a locus of impedance known as a Wessel plot;

FIG. 7 is a flowchart of a first specific example of a process foranalysing impedance measurements to allow assessment of venousinsufficiency;

FIG. 8 is a flowchart of a second specific example of a process foranalysing impedance measurements to allow assessment of venousinsufficiency;

FIG. 9 is a flowchart of a third specific example of a process foranalysing impedance measurements to allow assessment of venousinsufficiency;

FIG. 10 is a flowchart of a fourth specific example of a process foranalysing impedance measurements to allow assessment of venousinsufficiency; and,

FIG. 11 is a flowchart of a fifth specific example of a process foranalysing impedance measurements to allow assessment of venousinsufficiency.

DETAILED DESCRIPTION OF THE DRAWINGS

An example of apparatus suitable for performing an analysis of asubject's bioelectric impedance will now be described with reference toFIG. 1.

As shown the apparatus includes a measuring device 100 including aprocessing system 102, connected to one or more signal generators 117A,117B, via respective first leads 123A, 123B, and to one or more sensors118A, 118B, via respective second leads 125A, 125B. The connection maybe via a switching device, such as a multiplexer, although this is notessential.

In use, the signal generators 117A, 117B are coupled to two firstelectrodes 113A, 113B, which therefore act as drive electrodes to allowsignals to be applied to the subject S, whilst the one or more sensors118A, 118B are coupled to the second electrodes 115A, 115B, whichtherefore act as sense electrodes, to allow signals induced across thesubject S to be sensed.

The signal generators 117A, 117B and the sensors 118A, 118B may beprovided at any position between the processing system 102 and theelectrodes 113A, 113B, 115A, 115B, and may therefore be integrated intothe measuring device 100.

However, in one example, the signal generators 117A, 117B and thesensors 118A, 118B are integrated into an electrode system, or anotherunit provided near the subject S, with the leads 123A, 123B, 125A, 125Bconnecting the signal generators 117A, 117B and the sensors 118A, 118Bto the processing system 102. By performing this, the length of anyconnections between the signal generators 117A, 117B and the sensors118A, 118B, and the corresponding electrodes 113A, 113B, 115A, 115B canbe reduced. This minimises any parasitic capacitances between theconnections, the connections and the subject, and the connections andany surrounding articles, such as a bed on which the subject isprovided, thereby reducing measurement errors.

The above described system can be described as a two channel device,with each channel being designated by the suffixes A, B respectively.The use of a two channel device is for the purpose of example only, andany number of channels may be provided, as required.

An optional external interface 103 can be used to couple the measuringdevice 100, via wired, wireless or network connections, to one or moreperipheral devices 104, such as an external database or computer system,barcode scanner, or the like. The processing system 102 will alsotypically include an I/O device 105, which may be of any suitable formsuch as a touch screen, a keypad and display, or the like.

In use, the processing system 102 is adapted to generate controlsignals, which cause the signal generators 117A, 117B to generate one ormore alternating signals, such as voltage or current signals of anappropriate waveform, which can be applied to a subject S, via the firstelectrodes 113A, 113B. The sensors 118A, 118B then determine the voltageacross or current through the subject S, using the second electrodes115A, 115B and transfer appropriate signals to the processing system102.

Accordingly, it will be appreciated that the processing system 102 maybe any form of processing system which is suitable for generatingappropriate control signals and at least partially interpreting themeasured signals to thereby determine the subject's bioelectricalimpedance, and optionally determine other information such indicators ofthe presence, absence or degree of venous insufficiency, otherconditions, or the like.

The processing system 102 may therefore be a suitably programmedcomputer system, such as a laptop, desktop, PDA, smart phone or thelike. Alternatively the processing system 102 may be formed fromspecialised hardware, such as an FPGA (field programmable gate array),or a combination of a programmed computer system and specialisedhardware, or the like, as will be described in more detail below.

In use, the first electrodes 113A, 113B are positioned on the subject toallow one or more signals to be injected into the subject S. Thelocation of the first electrodes will depend on the segment of thesubject S under study. Thus, for example, the first electrodes 113A,113B can be placed on the thoracic and neck region of the subject S toallow the impedance of the chest cavity to be determined for use incardiac function analysis. Alternatively, positioning electrodes on thewrist and ankles of a subject allows the impedance of limbs and/or theentire body to be determined, for use in oedema analysis, assessment ofvenous insufficiency, or the like.

Once the electrodes are positioned, one or more alternating signals areapplied to the subject S, via the first electrodes 113A, 113B. Thenature of the alternating signal will vary depending on the nature ofthe measuring device and the subsequent analysis being performed.

For example, the system can use Bioimpedance Analysis (BIA) in which asingle low frequency signal is injected into the subject S, with themeasured impedance being used directly in the determination ofbiological parameters, such as extracellular fluid levels, which can beindicative of oedema, and hence of venous insufficiency.

In one example, the applied signal has a relatively low frequency, suchas below 100 kHz, more typically below 50 kHz and more preferably below10 kHz. In this instance, such low frequency signals can be used as anestimate of the impedance at zero applied frequency, commonly referredto as the impedance parameter value R₀, which is in turn indicative ofextracellular fluid levels.

Alternatively, the applied signal can have a relatively high frequency,such as above 200 kHz, and more typically above 500 kHz, or 1000 kHz. Inthis instance, such high frequency signals can be used as an estimate ofthe impedance at infinite applied frequency, commonly referred to as theimpedance parameter value R_(∞) which is in turn indicative of acombination of the extracellular and intracellular fluid levels, as willbe described in more detail below.

In contrast Bioimpedance Spectroscopy (BIS) devices perform impedancemeasurements at multiple frequencies over a selected frequency range.Whilst any range of frequencies may be used, typically frequencies rangefrom very low frequencies (4 kHz) to higher frequencies (15000 kHz).Similarly, whilst any number of measurements may be made, in one examplethe system can use 256 or more different frequencies within this range,to allow multiple impedance measurements to be made within this range.

When impedance measurements are made at multiple frequencies, these canbe used to derive one or more impedance parameter values, such as valuesof R₀, Z_(c), R_(∞), which correspond to the impedance at zero,characteristic and infinite frequencies. These can in turn be used todetermine information regarding both intracellular and extracellularfluid levels, as will be described in more detail below.

A further alternative is for the system to use Multiple FrequencyBioimpedance Analysis (MFBIA) in which multiple signals, each having arespective frequency are injected into the subject S, with the measuredimpedances being used in the assessment of fluid levels. In one example,four frequencies can be used, with the resulting impedance measurementsat each frequency being used to derive impedance parameter values, forexample by fitting the measured impedance values to a Cole model, aswill be described in more detail below. Alternatively, the impedancemeasurements at each frequency may be used individually or incombination.

Thus, the measuring device 100 may either apply an alternating signal ata single frequency, at a plurality of frequencies simultaneously, or anumber of alternating signals at different frequencies sequentially,depending on the preferred implementation. The frequency or frequencyrange of the applied signals may also depend on the analysis beingperformed.

In one example, the applied signal is generated by a voltage generator,which applies an alternating voltage to the subject S, althoughalternatively current signals may be applied.

In one example, the voltage source is typically symmetrically and/ordifferentially arranged, with each of the signal generators 117A, 117Bbeing independently controllable, to allow the potential across thesubject to be varied. This can be performed to reduce the effects of anyimbalance, which occurs when the voltages sensed at the electrodes areunsymmetrical (a situation referred to as an “imbalance”). In thisinstance, any difference in the magnitude of signals within the leadscan lead to differing effects due to noise and interference.

Whilst applying the voltage symmetrically, can reduce the effect, thisis not always effective if the electrode impedances for the two driveelectrodes 113A, 113B are unmatched, which is typical in a practicalenvironment. However, by adjusting the differential drive voltagesapplied to each of the drive electrodes 113A, 113B, this compensates forthe different electrode impedances, and restores the desired symmetry ofthe voltage at the sense electrodes 115A, 115B. This can be achieved bymeasuring the voltages at the sense electrodes, and then adjusting themagnitude and/or phase of the applied signal to thereby balance themagnitude of the sensed voltages. This process is referred to herein asbalancing and in one example is performed by minimizing the magnitude ofany common mode signal.

A potential difference and/or current is measured between the secondelectrodes 115A, 115B. In one example, the voltage is measureddifferentially, meaning that each sensor 118A, 118B is used to measurethe potential at each second electrode 115A, 115B and therefore needonly measure half of the potential as compared to a single ended system.

The acquired signal and the measured signal will be a superposition ofpotentials generated by the human body, such as the ECG(electrocardiogram), potentials generated by the applied signal, andother signals caused by environmental electromagnetic interference.Accordingly, filtering or other suitable analysis may be employed toremove unwanted components.

The acquired signal is typically demodulated to obtain the impedance ofthe system at the applied frequencies. One suitable method fordemodulation of superposed frequencies is to use a Fast FourierTransform (FFT) algorithm to transform the time domain data to thefrequency domain. This is typically used when the applied current signalis a superposition of applied frequencies. Another technique notrequiring windowing of the measured signal is a sliding window FFT.

In the event that the applied current signals are formed from a sweep ofdifferent frequencies, then it is more typical to use a signalprocessing technique such as correlating the signal. This can beachieved by multiplying the measured signal with a reference sine waveand cosine wave derived from the signal generator, or with measured sineand cosine waves, and integrating over a whole number of cycles. Thisprocess, known variously as quadrature demodulation or synchronousdetection, rejects all uncorrelated or asynchronous signals andsignificantly reduces random noise.

Other suitable digital and analogue demodulation techniques will beknown to persons skilled in the field.

In the case of BIS, impedance or admittance measurements can bedetermined from the signals at each frequency using the recorded voltageacross and current flow through the subject. The demodulation algorithmcan then produce an amplitude and phase signal at each frequency. Thiscan then be used to derive one or more impedance parameter values, ifrequired.

As part of the above described process, the position of the secondelectrodes may be measured and recorded. Similarly, other parametersrelating to the subject (subject parameters) may be recorded, such asthe height, weight, age, sex, health status, any interventions and thedate and time on which they occurred. Other information, such as currentmedication, may also be recorded. This can then be used in performingfurther analysis of the impedance measurements, so as to allowdetermination of the presence, absence or degree of venous insufficiencyand/or oedema, to assess body composition, or the like.

An example of the process of analysing impedance measurements operationof the apparatus of FIG. 1 to perform this will now be described withreference to FIG. 2.

At step 200, at least one first impedance value indicative of theimpedance of at least one segment of the subject's leg is determined.This may be achieved by having the signal generators 117A, 117B, applyat least one first signal to the subject S, via the first electrodes113A, 113B, with voltage signals being measured across the subject S bythe sensors 118A, 118B, via the second electrodes 115A, 115B. Anindication of the current flow through and voltage across the subject isprovided to the processing system 102, allowing the impedance, or animpedance parameter value to be determined.

At step 210, an indicator is determined using the first impedance. Theindicator is typically indicative of the extracellular fluid levelswithin the subject. Accordingly, in one example, the impedancemeasurement is performed at a single low frequency, such as below 100kHz, and in one example, at 5 kHz, allowing the indicator to be based onthe measured value directly. Alternatively, multiple measurements may beperformed at multiple frequencies, with the indicator being based on anappropriate impedance parameter value derived therefrom, such as theimpedance at zero applied frequency R₀, as will be described in moredetail below.

Optionally, at step 220, the indicator can be used in the assessment ofvenous insufficiency, or other conditions, such as oedema orlymphoedema. In this regard, high extracellular fluid levels in the legsegment are indicative of oedema in the leg, which is in turn anindicator that venous insufficiency may be present. In one example, theindicator can be compared to a reference, such as an oedema reference,to allow the presence, absence or degree of oedema to be determined, aswill be described in more detail below.

As the determination of the presence of oedema alone may not beconclusive as to the presence, absence or degree of venousinsufficiency, or lymphoedema, additional steps may optionally beperformed.

In one example, at step 230, the subject can be treated for venousinsufficiency. This can be performed in any one of a number of manners,such as by performing ablation, or the like. Following this, at step240, the impedance measurement described above is repeated to allow apost-treatment indicator to be determined. Any difference between thepre-treatment indicator determined prior to treatment, and thepost-treatment indicator, can be used to determine if there has been areduction in the extra-cellular fluid levels. Any reduction in fluidlevels indicates that the treatment has been at least partiallysuccessful, thereby allowing the presence of venous insufficiency to beconfirmed at step 250.

In this example, both measurements are typically made with the subjectin a standing or equivalent position, such as leaning or sitting withtheir leg hanging in a substantially vertical position, to therebyenhance the impact of blood pooling caused by venous insufficiency onextracellular fluid levels. For the purpose of the remainingdescription, the term standing will be understood to encompass anyposition that maximises or enhances pooling of blood in the subject'sleg.

In another example, at step 260, the subject is reorientated from anorientation used to determine the first indicator, allowing a change inindicator between different orientations to be determined at step 270.

Thus, the first indicator can be determined with the subject provided ina first orientation, to allow a baseline reading to be established. Inone example, this is performed with the subject in an orientationdesigned to reduce or minimise blood pooling, such as with the subjectin a supine position, and optionally with their leg elevated to a heightof up to 20 cm above the level of their heart. For the purpose of theremaining description, the term supine will be understood to encompassany position that minimises pooling of blood in the subject's leg.

The subject then stands, leans or sits with their leg hanging in asubstantially vertical position, allowing a second indicator to bedetermined, with a change in indicator values being indicative of thechange of extracellular fluid levels within the leg, which in turn canbe used in venous insufficiency assessment.

Alternatively, the subject can be allowed to stand to allow pooling ofblood. Following this, the subject is returned to the supine positionallowing the indicator value to be monitored. The time taken for thisreturn to the baseline, or to within a range of the threshold, can thenbe used in venous insufficiency assessment.

In another example, at step 280, second impedance measurements areperformed to allow an index to be determined at step 290. The index istypically indicative of a ratio between intracellular and extracellularfluid levels in the leg, or a leg segment, which can in turn be used toassess the presence of lymphoedema. Being able to distinguish betweenoedema and lymphoedema can assist in assessing venous insufficiency.

In the above described examples, the measurements are performed on thesubject's leg as this maximises the effect of any blood pooling, therebymaximising the effectiveness of the measurement procedure to determineindicators that can be used in identifying venous insufficiency.However, if the technique is being used for other identifying conditionssuch as lymphoedema, then the process can be applied to other bodysegments, such as arms, as will be described in more detail below.

A specific example of the apparatus will now be described in more detailwith respect to FIG. 3.

In this example, the measuring system 300 includes a computer system 310and a separate measuring device 320. The measuring device 320 includes aprocessing system 330 coupled to an interface 321 for allowing wired orwireless communication with the computer system 310. The processingsystem 330 may also be optionally coupled to one or more stores, such asdifferent types of memory, as shown at 322, 323, 324, 325, 326.

In one example, the interface is a Bluetooth stack, although anysuitable interface may be used. The memories can include a boot memory322, for storing information required by a boot-up process, and aprogrammable serial number memory 323, that allows a device serialnumber to be programmed. The memory may also include a ROM (Read OnlyMemory) 324, flash memory 325 and EPROM (Electronically ProgrammableROM) 326, for use during operation. These may be used for example tostore software instructions and to store data during processing, as willbe appreciated by persons skilled in the art.

A number of analogue to digital converters (ADCs) 327A, 327B, 328A, 328Band digital to analogue converters (DACs) 329A, 329B are provided forcoupling the processing system 330 to the sensors 118A, 118B and thesignal generators 117A, 117B, as will be described in more detail below.

A controller, such as a microprocessor, microcontroller or programmablelogic device, may also be provided to control activation of theprocessing system 330, although more typically this is performed bysoftware instructions executed by the processing system 330.

An example of the computer system 310 is shown in FIG. 4. In thisexample, the computer system 310 includes a processor 400, a memory 401,an input/output device 402 such as a keyboard and display, and anexternal interface 403 coupled together via a bus 404, as shown. Theexternal interface 403 can be used to allow the computer system tocommunicate with the measuring device 320, via wired or wirelessconnections, as required, and accordingly, this may be in the form of anetwork interface card, Bluetooth stack, or the like.

In use, the computer system 310 can be used to control the operation ofthe measuring device 320, although this may alternatively be achieved bya separate interface provided on the measuring device 300. Additionally,the computer system 310 can be used to allow at least part of theanalysis of the impedance measurements to be performed.

Accordingly, the computer system 310 may be formed from any suitableprocessing system, such as a suitably programmed PC, Internet terminal,lap-top, hand-held PC, smart phone, PDA, server, or the like,implementing appropriate applications software to allow required tasksto be performed.

In contrast, the processing system 330 typically performs specificprocessing tasks, to thereby reduce processing requirements on thecomputer system 310. Thus, the processing system typically executesinstructions to allow control signals to be generated for controllingthe signal generators 117A, 117B, as well as the processing to determineinstantaneous impedance values.

In one example, the processing system 330 is formed from customhardware, or the like, such as a Field Programmable Gate Array (FPGA),although any suitable processing module, such as a magnetologic module,may be used.

In one example, the processing system 330 includes programmablehardware, the operation of which is controlled using instructions in theform of embedded software instructions. The use of programmable hardwareallows different signals to be applied to the subject S, and allowsdifferent analysis to be performed by the measuring device 320. Thus,for example, different embedded software would be utilised if the signalis to be used to analyse the impedance at a number of frequenciessimultaneously as compared to the use of signals applied at differentfrequencies sequentially.

The embedded software instructions used can be downloaded from thecomputer system 310. Alternatively, the instructions can be stored inmemory such as the flash memory 325 allowing the instructions used to beselected using either an input device provided on the measuring device320, or by using the computer system 310. As a result, the computersystem 310 can be used to control the instructions, such as the embeddedsoftware, implemented by the processing system 330, which in turn altersthe operation of the processing system 330.

Additionally, the computer system 310 can operate to analyse impedancedetermined by the processing system 330, to allow biological parametersto be determined.

Whilst an alternative arrangement with a single processing system may beused, the division of processing between the computer system 310 and theprocessing system 330 can provide some benefits.

Firstly, the use of the processing system 330 more easily allows thecustom hardware configuration to be adapted through the use ofappropriate embedded software. This in turn allows a single measuringdevice to be used to perform a range of different types of analysis.

Secondly, the use of a custom configured processing system 330 reducesthe processing requirements on the computer system 310. This in turnallows the computer system 310 to be implemented using relativelystraightforward hardware, whilst still allowing the measuring device toperform sufficient analysis to provide interpretation of the impedance.This can include for example generating a “Wessel” plot, using theimpedance values to determine parameters relating to cardiac function,as well as determining the presence or absence of lymphoedema.

Thirdly, this allows the measuring device 320 to be updated. Thus forexample, if an improved analysis algorithm is created, or an improvedcurrent sequence determined for a specific impedance measurement type,the measuring device can be updated by downloading new embedded softwarevia flash memory 325 or the external interface 321.

In use, the processing system 330 generates digital control signals,which are converted to analogue voltage drive signals V_(D) by the DACs329, and transferred to the signal generators 117. Analogue signalsrepresenting the current of the drive signal I_(D) applied to thesubject and the subject voltage V_(S) measured at the second electrodes115A, 115B are received from the signal generators 117 and the sensors118 and are digitised by the ADCs 327, 328. The digital signals can thenbe returned to the processing system 330 for preliminary analysis.

In this example, a respective set of ADCs 327, 328, and DACs 329 areused for each of two channels, as designated by the reference numeralsuffixes A, B respectively. This allows each of the signal generators117A, 117B to be controlled independently and for the sensors 118A, 118Bto be used to detect signals from the electrodes 115A, 115Brespectively. This therefore represents a two channel device, eachchannel being designated by the reference numerals A, B.

In practice, any number of suitable channels may be used, depending onthe preferred implementation. Thus, for example, it may be desirable touse a four channel arrangement, in which four drive and four senseelectrodes are provided, with a respective sense electrode and driveelectrode pair being coupled to each limb. In this instance, it will beappreciated that an arrangement of eight ADCs 327, 328, and four DACs329 could be used, so each channel has respective ADCs 327, 328, andDACs 329. Alternatively, other arrangements may be used, such as throughthe inclusion of a multiplexing system for selectively coupling atwo-channel arrangement of ADCs 327, 328, and DACs 329 to a four channelelectrode arrangement, as will be appreciated by persons skilled in theart.

An example of the process for performing impedance measurements will nowbe described with reference to FIG. 5.

At step 500, the electrodes are positioned on the subject as required.The general arrangement to allow impedance of a leg to be determined isto provide drive electrodes 113A, 113B on the hand at the base of theknuckles and on the feet at the base of the toes, on the side of thebody being measured. Sense electrode 115A are also positioned at thefront of the ankle on the leg being measured, with the sense electrode115B being positioned anywhere on the contra-lateral leg.

It will be appreciated that this configuration uses the theory of equalpotentials, allowing the electrode positions to provide reproducibleresults for impedance measurements. This is advantageous as it greatlyreduces the variations in measurements caused by poor placement of theelectrodes by the operator.

Alternatively however other arrangements can be used. Thus for example,the sense electrodes can be provided anywhere on the leg of interest,allowing the impedance measurements to be made along the entire leg, orfor a part of the leg (generally referred to as a leg segment), such asa calf segment, or the like.

At step 510, an impedance measurement type is selected using thecomputer system 310, allowing the processing system to determine animpedance measurement protocol, and configure the processing system 330accordingly. This is typically achieved by configuring firmware orsoftware instructions within the processing system 330, as describedabove.

At step 520, the processing system 300 selects a next measurementfrequency f_(i), and causes the signal generators 117A, 117B to apply afirst signal to the subject at the selected frequency at step 530. Atstep 540, the signal generators 117A, 117B and sensors 118A, 118Bprovide an indication of the current through and the voltage across theleg segment to the processing system 330.

At step 550, the processing system 330 determines if all frequencies arecomplete, and if not returns to step 520 to select the next measurementfrequency. At step 560, one or more measured impedance values aredetermined, by the computer system 310, the processing system 330, or acombination thereof, using the techniques described above. One or moreimpedance parameter values may optionally be derived at step 570.

In this regard, FIG. 6A is an example of an equivalent circuit thateffectively models the electrical behaviour of biological tissue. Theequivalent circuit has two branches that represent current flow throughextracellular fluid and intracellular fluid, respectively. Theextracellular fluid component of biological impedance is represented byan extracellular resistance R_(e), whilst the intracellular fluidcomponent is represented by an intracellular resistance R_(i) and acapacitance C representative of the cell membranes.

The relative magnitudes of the extracellular and intracellularcomponents of impedance of an alternating current (AC) are frequencydependent. At zero frequency the capacitor acts as a perfect insulatorand all current flows through the extracellular fluid, hence theresistance at zero frequency, R₀, equals the extracellular resistanceR_(e). At infinite frequency the capacitor acts as a perfect conductorand the current passes through the parallel resistive combination. Theresistance at infinite frequency R_(∞) is given by:

$\begin{matrix}{R_{\infty} = \frac{R_{e}R_{i}}{R_{e} + R_{i}}} & (1)\end{matrix}$

Accordingly, the impedance of the equivalent circuit of FIG. 6A at anangular frequency ω, where ω=2π*frequency, is given by:

$\begin{matrix}{Z = {R_{\infty} + \frac{R_{0} - R_{\infty}}{1 + \left( {{j\omega}\; \tau} \right)}}} & (2)\end{matrix}$

where:

-   -   R_(∞)=impedance at infinite applied frequency    -   R₀=impedance at zero applied frequency=R_(e) and,    -   τ is the time constant of the capacitive circuit.

However, the above represents an idealised situation which does not takeinto account the fact that the cell membrane is an imperfect capacitor.Taking this into account leads to a modified model in which:

$\begin{matrix}{Z = {R_{\infty} + \frac{R_{0} - R_{\infty}}{1 + \left( {{j\omega}\; \tau} \right)^{({1 - \alpha})}}}} & (3)\end{matrix}$

where:

-   -   α has a value between 0 and 1 and can be thought of as an        indicator of the deviation of a real system from the ideal        model.

The values of impedance parameters R₀, R_(∞) or Z_(c) may be determinedin any one of a number of manners such as by:

-   -   estimating values based on impedance measurements performed at        selected respective frequencies;    -   solving simultaneous equations based on the impedance values        determined at different frequencies;    -   using iterative mathematical techniques;    -   extrapolation from a “Wessel plot” similar to that shown in FIG.        6B;    -   performing a function fitting technique, such as the use of a        polynomial function.

For example, the Wessel plot is often used in BIS (BioimpedanceSpectroscopy) Bioimpedance Spectroscopy (BIS) devices, which performmultiple measurements over a range of frequencies, such as from 4 kHz to1000 kHz, using 256 or more different frequencies within this range. Aregression procedure is then used to fit the measured data to thetheoretical semi-circular locus, allowing values for R_(∞) and R₀ to becalculated.

The regression analysis is computationally expensive, requiring a devicewith significant processing power to perform the calculations, which inturn results in relatively high power usage by the apparatus, requiringa larger battery, and adding to the weight and size of the apparatus.

A further issue is that a large number of data points are required toperform the regression analysis, and as measurements are typicallyperformed at each frequency sequentially, the measurement process takesa significant amount of time, such as several seconds. This isundesirable as remaining still for long periods of time can causediscomfort for the subject. Additionally, the subject may move duringthe measurement procedure, which can affect the measured impedancevalues, for example due to changes in capacitive and/or inductivecoupling between the subject and environment, leads and electrodes. Thiscan lead to inaccuracies in the measured values.

A circle may be described by the equation:

(x−i)²+(y−j)² =r ²  (3)

-   -   where: i and j are the centre of the circle and r is the radius.

Additionally, a circle may be uniquely defined by the co-ordinates ofthree points (x₁₋₃, y₁₋₃) located on the locus, as shown in FIG. 4.Accordingly, three simultaneous equations can be defined, one for eachof three loci that describe the circle that fits these points, as shownby equations (4) below.

(x ₁ −i)²+(y ₁ −j)² =r ²

(x ₂ −i)²+(y ₂ −j)² =r ²

(x ₃ −i)²+(y ₃ −j)² =r ²  (4)

Solving these three simultaneous equations allows calculation of theradius (r) and the co-ordinates of the centre of the circle (i, j). Fromthese data, R₀ and R_(∞) are readily computed from geometric firstprinciples.

Accordingly, this technique allows a value for R₀ and optionally R_(∞)to be derived in a computationally less expensive manner than if aregression analysis is performed. Additionally, this also requires areduced number of data points. This allows a value of R₀ to bedetermined more rapidly, and with a more basic processor than can beachieved using BIS and regression analysis, which in turn renders thedevice required to determine a value of R₀ less expensive tomanufacture.

In particular, this is achieved by performing impedance measurements atleast three frequencies. Indications of the signals are used todetermine first and second impedance parameter values at each of thefrequencies. The nature of the impedance parameter values will varydepending on the preferred implementation. Thus, for example theimpedance parameter values could include magnitude and phase informationrelating to the measured signals. However, in one example the impedanceparameter values are indicative of the resistance and reactance, asderived from the magnitude and phase signals.

Once this is completed, simultaneous equations are solved using thefirst and second impedance parameter values determined at each of thethree frequencies, thereby allowing circle parameters to be determined.The circle parameters are used to define a locus corresponding to atleast part of an arc of a circle in a space defined by the parametervalues. Thus, in one example, the simultaneous equations represent acircular locus provided in a reactance/resistance space, similar to theWessel plot described above.

Theoretical impedance parameter values, such as R₀ and R_(∞) can then bedetermined from the circle parameters.

One potential disadvantage of the use of simultaneous equations is thatif one of the impedance measurements is inaccurate for any reason, thiscan lead to a large deviation in the calculated value of R₀.Accordingly, in one example, impedance measurements are performed atmore than three frequencies, with circle parameters for all possiblecombinations of impedance measurements at three frequencies beingcalculated. The average can be provided along with the standarddeviation as a measure of the goodness of fit of the data to the Colemodel. In the event that one of the measurements is inaccurate, this canbe accounted for by excluding one or more outlier measurements, such asmeasurements that deviates the greatest amount from the mean, ormeasurements differing by more than a set number of standard deviationsfrom the mean, allowing the mean to be recalculated, thereby providingmore accurate values.

Whilst this process uses additional measurements, such as four or fivemeasurements, this is still significantly less than the 256 or morefrequencies typically performed using a BIS measurement protocol,allowing the measurement process to be performed more quickly.

In one example, the frequencies used are in the range 0 kHz to 1000 kHz,and in one specific example, four measurements are recorded atfrequencies of 25 kHz, 50 kHz, 100 kHz, and 200 kHz, although anysuitable measurement frequencies can be used.

A further alternative for determining impedance parameter values such asR₀ and R_(∞) is it perform impedance measurements at a single frequency,and use these as an estimate of the parameter values. In this instance,measurements performed at a single low frequency can be used to estimateR₀, whilst measurements at a single high frequency can be used toestimate R_(∞).

The above described equivalent circuit models the resistivity as aconstant value and does not therefore accurately reflect the impedanceresponse of a subject, and in particular does not accurately model thechange in orientation of the erythrocytes in the subject's blood stream,or other relaxation effects. To more successfully model the electricalconductivity of the human body, an improved CPE based model mayalternatively be used.

In any event, it will be appreciated that any suitable technique fordetermination of the parameter values such as R₀, Z_(c) and R_(∞) may beused.

A first specific example of a process for analysing impedancemeasurements to allow assessment of venous insufficiency will now bedescribed with reference to FIG. 7.

In this example, at step 700, at least one first impedance value isdetermined using the method described above. The measurement istypically performed with the subject in a specific orientation, such asin a supine or standing position. This is performed to either maximiseor minimise the effect of blood pooling, and this will depend on theanalysis performed.

In this first specific example, the subject is made to stand for a settime period such as between five and fifteen minutes to maximize theeffect of any blood pooling. In general, a marked increase in bloodpooling is achieved after five minutes, with the blood levels reaching arelatively static maximum after approximately fifteen minutes.Accordingly, whilst it is preferable for the subject to stand forfifteen minutes to thereby maximise blood pooling, even after fiveminutes sufficient pooling occurs to allow measurements to be performed.It will be appreciated from this that the length of time selected maydepend on factors such as the amount of time available for themeasurement process and the ability of the subject to remain in standingposition.

Furthermore, the subject may be required to lay in a supine position fora set time period, such as five to fifteen minutes prior to standing.This can be performed to minimise any blood pooling before standing, soas to provide a more accurate baseline status for the subject prior tomeasurements being performed. Again, a marked reduction in pooling isachieved after five minutes, with the level of pooling typicallyreaching a reasonably static minimum after approximately fifteenminutes, so the length of time used will depend on factors such as theamount of time available to make a measurement.

At step 710 an impedance parameter value R₀ is optionally determined.This can be performed if multiple impedance values are determined.Otherwise, a single impedance measurement can be made at a lowfrequency, such as below 10 kHz, as this provides a reasonably closeapproximation of R₀.

At step 720, an indicator that is indicative of the extracellular R_(e)fluid levels within the subject is determined, with this being displayedto the user at step 730.

The indicator can be any form of suitable indicator such as a numericalvalue based on the value of the impedance parameter value R₀. Theindicator may also be scaled to provide a numerical value that isindicative of the presence, absence or degree of venous insufficiency oroedema. The indicator can also be based on the results of a comparisonof a numerical value to a reference, such as an oedema reference.

The oedema reference could be any suitable form of reference. Thus, inone example, the oedema reference can be based on an equivalentimpedance parameter value determined for a different limb of thesubject, such as an arm. This is possible, as, for a subject notsuffering from venous insufficiency, there is a predictable relationshipbetween the extracellular fluid levels between different limbs. Thus,for example, if the subject is suffering from a condition other thanvenous insufficiency, which causes a general change in extracellularfluid levels, then this should affect body segments in an assessablemanner, thereby allowing venous insufficiency to be identified.

Minor variations in tissue may occur between different body segments ina healthy subject, and this can be accounted for by providing atolerance to the comparison. Thus, for example, this could take intoaccount naturally expected variations between different limbs in normalhealthy subjects, for example due to limb dominance, previous analysisfor the subject, or the like. The tolerance may also depend on a numberof factors, such as the subject's age, weight, sex and height, and againa respective range can be selected based on these factors.

Alternatively, the oedema reference can be based on a reference derivedfrom sample populations, or the like. The oedema reference can beselected based on the subject parameters, so that the value of theindicator is compared to values of the indicator derived from a study ofa sample population of other individuals having similar subjectparameters.

As a further alternative, the oedema reference can be based on apreviously measured reference for the subject, for example determinedbefore the subject suffered from venous insufficiency or oedema. Thisallows a longitudinal analysis to be performed, thereby allowing theonset or progression of venous insufficiency to be assessed.

The indicator can additionally and/or alternatively be displayed on agraphical linear or non-linear scale, with the position of a pointer onthe scale being indicative of extracellular fluid levels and or thepresence, absence or degree of oedema or venous insufficiency. In oneexample, the linear scale can include thresholds at values representingranges indicative of the presence or absence of oedema or venousinsufficiency, as derived from sample population data, or otherreferences.

At step 740, the user can use the indicator to assess whether furtherinvestigation is required. In this regard, a high extra-cellular fluidlevel indicative of the presence of oedema is a good indication that thesubject has venous insufficiency, but this may need to be confirmed withfurther measurements, and/or analysis.

The above described example allows for a rapid assessment of thepresence of venous insufficiency. This can be performed using BIA, whichallows relatively simple apparatus and processing to be used, therebyreducing the cost of equipment required to assess venous insufficiencycompared to more complex techniques. Despite this, the process is morereliable than current non-invasive techniques such as SPG and APG. Inthis regard, changes in fluid levels can typically be detected usingimpedance measurements before the fluid level changes have a noticeableimpact on limb volume, thereby making the impedance measurement processmore sensitive than other techniques such as SPG or APG.

Examples for performing further investigation will now be described inmore detail.

In the specific example of FIG. 8, at step 800 a first indicator valueis determined with the subject in a standing position, as described withrespect to FIG. 7, to maximise blood pooling. This is performed beforethe subject is treated so that the first indicator acts as apre-treatment indicator. At step 810, the subject is treated for venousinsufficiency, by performing ablation, or the like. Following this, atstep 820, a second indicator value is determined using a similartechnique, (i.e. with the subject in a standing position) which acts asa post-treatment indicator.

The processing system 102 then determines any difference between thefirst and second indicator values at step 830, with the difference beingcompared to a reference, such as a treatment reference at step 840,thereby allowing the relevance of any change to be assessed. If thecomparison indicates that there is a reduction in the extra-cellularfluid levels greater than a threshold amount, then this indicates thatthe treatment is successful or has at least had an impact, therebyallowing the presence of venous insufficiency to be confirmed at step850. The magnitude of any difference may also be used to determine thedegree of any venous insufficiency, and/or the effectiveness of thetreatment.

Again, the treatment reference can be derived in any one of a number ofmanners. For example, treatment reference can be obtained from datacollected from a sample population of subjects, which acts as a pool ofdata from which normalised expected differences for successfullytreated, untreated and/or healthy subjects can be determined. Thetreatment reference is then generated by selecting reference values thatare determined to be relevant to the test subject based on the subjectparameters such as age, sex, height, weight, race, interventions, or thelike.

In this instance, given a preliminary indication that venousinsufficiency is present following the procedure of FIG. 7, treatment ofthe subject is performed, with the presence of venous insufficiencybeing confirmed if the treatment is successful in the sense that itresults in a reduction in extra-cellular fluid levels. This thereforeallows a more reliable assessment of venous insufficiency, butadvantageously also simultaneously treats the venous insufficiency,ensuring that the subject is treated as rapidly as possible, withouthaving to await further analysis. In the instance that the subject doesnot have venous insufficiency, then there is no negative effect ofperforming the treatment. It will also be appreciated that this allowsthe analysis to be confirmed using the same apparatus as used to performthe initial assessment, thereby simplifying the analysis for therelevant health professional performing the assessment.

In the specific example of FIG. 9, at step 900 a first indicator valueis determined with the subject in a supine position. This measurement istypically performed after the subject has been allowed to rest for someset time, such as five to fifteen minutes. This reduces the effect ofany blood pooling, allowing a baseline reading to be established. Thesubject then stands for a predetermined time period, such as five tofifteen minutes, to maximize blood pooling before a second indicatorvalue is determined using the technique described above, at step 910.Again, the first and second indicator values are indicative ofextra-cellular fluid levels, and therefore could be based on one or morelow frequency impedance measurements or the impedance parameter valueR₀, as derived from impedance measurements in some manner.

At step 920, the processing system 102 then determines any differencebetween the first and second indicator values, with the difference beingcompared to a reference, such as a pooling reference, at step 930.

Again, the pooling reference can be based on similar indicator valuesderived from sample populations, or the like. Alternatively, the poolingreference can be based on first and second indicator values previouslydetermined for the subject, for example prior to the onset of venousinsufficiency, allowing longitudinal analysis to be performed.

In one example, the reference is determined as a percentage change fromthe baseline reading, so that a change of less than a predeterminedamount, such as 15%, indicates that the subject does not have venousinsufficiency. For a percentage change greater than the predeterminedamount, such as 15%, this indicates that the level of pooling isabnormal, and hence that the subject may have venous insufficiency, withthe magnitude of the percentage change being indicative of the degree ofvenous insufficiency. Thus, for example, a change of greater than 20%,would typically be indicative of venous insufficiency.

Results of the comparison can be displayed at step 940, to allow therelevance of any change to be assessed. In this regard, if thecomparison indicates that there is an increase in the extra-cellularfluid levels greater than an amount determined from the poolingreference, then this indicates that there is significant blood poolingwithin the subject, which is in turn indicative of venous insufficiency.It will be appreciated from this, that the magnitude of the differencebetween the first and second indicator values can be indicative of thedegree of venous insufficiency.

In this instance, given a preliminary indication that venousinsufficiency is present following the procedure of FIG. 7, the subjectis reorientated and the measurement re-performed. In this regard, if theindicator derived in the process of FIG. 7 is made in the standingposition, then this can act as the second indicator, with the subjectbeing reorientated to allow the first indicator to be determined.Accordingly, it will be appreciated that the terms “first” and “second”are used to identify respective indicators and do not necessarily implyor require an order to the measurements.

However, in general the first indicator is measured first to allow anaccurate baseline to be established, although this is not essential.This allows a more reliable assessment of venous insufficiency thanachievable with prior art techniques, and allows the analysis to beconfirmed using the same apparatus as used to perform the initialassessment. This also allows assessment to be confirmed withoutrequiring treatment of the subject, which can reduce the cost burden ofthe assessment.

In the specific example of FIG. 10, at step 1000 a first indicator valueis determined with the subject in a supine position. As in the previousexample, this is performed to allow a baseline reading to beestablished. The subject then stands for a predetermined time period,such as five to fifteen minutes, to maximize blood pooling at step 1010,before returning to a supine position to allow a second indicator valueto be determined using the technique described above, at step 1020.

At step 1030, the processing system 102 then determines any differencebetween the first and second indicator values, before determining if thedifference is below a reference, such as a return reference, at step1040. If not, the process returns to step 1020, allowing a new secondindicator to be determined.

The reference may be derived from sample populations, previousmeasurements for the subject, or the like. Alternatively, the referenceis deemed to be a certain percentage variation from the baselinereading. Thus, in this example, the time taken to return to within 5-10%of the baseline reading can be determined.

Steps 1020 to 1040 are repeated until the difference between the firstand second indicators is below the return reference. At step 1050, thelength of time taken for the difference to fall below the poolingreference is determined, with this being displayed to the user at step1060.

If the time taken to return to the baseline (or the reference), is lessthan a reference amount, such as fifteen minutes, then this isindicative that the subject does not have venous insufficiency. However,if the time taken is greater than the reference time, then this isindicative that the subject does have venous insufficiency.

In this regard, in a healthy subject, the amount of blood will return tothe baseline amount relatively quickly, whilst in a subject with venousinsufficiency, this can take several minutes. Accordingly, the timetaken for blood pooling in the leg to be reduced is in turn indicativeof the presence, absence or degree of venous insufficiency. The returnreference is used to take into account natural variation and to allowthe measurement to be performed in a reasonable time period.

In this instance, by measuring the time taken for the subject to returnto a baseline reading, this provides a direct correlation for theability of the venous system to counteract any blood pooling, which isdirectly indicative of the degree of venous insufficiency. Thistherefore provides an accurate technique for assessing the severity ofvenous insufficiency without requiring treatment or complex apparatus.

An example of a process for allowing oedema and lymphoedema to bedistinguished will now be described with reference to FIG. 11. In oneexample, this process can be used to help assess the presence of venousinsufficiency. For example, if measurements are performed on thesubject's leg, and it is determined that the subject has oedema but notlymphoedema, then this is indicative that the subject has venousinsufficiency. Alternatively however, this technique can be used todistinguish between oedema and lymphoedema in other body segments, suchas arms. This can be used in helping to identify optimum managementprogrammes depending on the conditions suffered by the subject.

Accordingly, for the purpose of this example, the technique will bedescribed as being generally applied to a body segment to allow oedemaand lymphoedema to be distinguished. It will be appreciated that in theevent that this technique is used for identifying venous insufficiency,then the process will be performed on the subject's leg, but that theprocess could also be applied to other body segments.

In the specific example of FIG. 11, at step 1100 impedance values aredetermined for the body segment at a number of different frequencies. Ifthis technique is being used to determine indicators that can be used inidentifying venous insufficiency, then these measurements are typicallyperformed with the subject in a standing position to maximise bloodpooling.

At step 1110, the processing system 102 determines values for theimpedance parameters R₀, R_(∞) as described in more detail above. Thus,this could be performed using regression analysis applied to BISmeasurements. Alternatively, the process could use MFBIA, and solving ofsimultaneous equations to determine the impedance parameter values.Other techniques could also be used as appropriate in which combinationsof individual measurements at selected frequencies are used. Thus, forexample, single measurements at low and high frequencies respectivelycould be used as an estimate of R₀ and R_(∞).

At step 1120, a first indicator value is determined using the impedanceparameter value R₀. It will be appreciated that this can alternativelybe derived from a single low frequency impedance measurement describedabove, although in another example, measurements at multiple frequenciescan be used for subsequent steps, in which case the need to makeadditional single frequency measurements can be avoided.

At step 1130, an index is determined for the body segment which providesan indication of the distribution between intra and extracellularfluids. In one example, the index is indicative of the ratio ofextracellular fluid to intracellular fluid R_(i)/R_(e). In this regard,using the values for the extracellular fluid resistance R_(e) andintracellular fluid resistance R_(i) above, the index I is given by theequation:

$\begin{matrix}{I = {\frac{R_{i}}{R_{e}} = \frac{R_{\infty}}{R_{0} - R_{\infty}}}} & (4)\end{matrix}$

At step 1140, the first indicator value is compared to a firstreference, such as the oedema reference described above, with theresults of the comparison allowing the presence of oedema to bedetermined.

At step 1150, the index value is compared to a second reference, withthe results of the comparison allowing determination of whether thesubject has lymphoedema. The second reference can be determined in anyone of a number of manners.

In one example, the index is compared to a reference index valuedetermined for another limb. This is possible, as, for a subject nothaving lymphoedema, there is generally a degree of similarity of intra-and extra-cellular fluid levels, even between different body segments.Typically minor variations in tissue will occur between different bodysegments, for example due to inherent differences between differenttypes of limb, or due to limb dominance, and this can be accounted forusing appropriate tolerances in a manner similar to that describedabove. Additionally, and/or alternatively, different references can beused, such as references derived from sample populations, previousmeasurements made for the subject, or the like.

The results of the comparison can be displayed to the user to allowassessment of whether the subject has oedema and/or lymphoedema.

In the event that measurements are performed on the subject's leg,whilst the subject is in a standing position, and this indicates thatthe subject is likely to have oedema which is not lymphoedema, then thisis indicative that the subject has venous insufficiency. In thisinstance, the magnitude of the indicator and index values can be used toassess the degree of venous insufficiency. Alternatively, this techniquecan be used on other parts of the body to distinguish between oedema andlymphoedema.

In a further example, the above described process can be repeated withthe subject in supine and standing positions. In this instance, changesin the indicator and index values can further assist in assessing thepresence, absence or degree of venous insufficiency.

In this example, whilst more complex BIS apparatus is required, this canprovide a more accurate indication of venous insufficiency severity thancan be achieved using the prior art or other techniques. Furthermore, byusing the BIS apparatus described above, the assessment can be performedrapidly, without requiring the subject to undergo exercise regimes,which may not be appropriate for some subjects.

In the above described examples, the term impedance generally refers toa measured impedance value or impedance parameter value derivedtherefrom. The term resistance refers to any measured value relating tothe impedance, such as admittance of reactance measurements.

The term processing system is intended to include any component capableof performing processing and can include any one or more of a processingsystem and a computer system.

Persons skilled in the art will appreciate that numerous variations andmodifications will become apparent. All such variations andmodifications which become apparent to persons skilled in the art,should be considered to fall within the spirit and scope that theinvention broadly appearing before described.

Features from different examples above may be used interchangeably whereappropriate. Thus, for example, multiple different indicators may bedetermined and compared to respective thresholds.

Furthermore, whilst the above examples have focussed on a subject suchas a human, it will be appreciated that the measuring device andtechniques described above can be used with any animal, including butnot limited to, primates, livestock, performance animals, such racehorses, or the like.

The above described processes can be used in determining biologicalindicators, which in turn can be used for diagnosing the presence,absence or degree of a range of conditions and illnesses, including, butnot limited to oedema, lymphodema, body composition, or the like.

Furthermore, whilst the above described examples have focussed on theapplication of a voltage signal to cause a current to flow through thesubject, this is not essential and the process can also be used whenapplying a current signal.

It will also be appreciated that the term impedance measurement coversadmittance and other related measurements.

1) A method for use in analysing impedance measurements performed on asubject, the method including, in a processing system: a) determining atleast one impedance value indicative of the impedance of at least oneleg segment of the subject; and, b) determining an indicator using theat least one impedance value, the indicator being indicative ofextracellular fluid levels in the at least one leg segment and beingused in the assessment of venous insufficiency. 2) A method according toclaim 1, wherein the method includes, in a processing system: a)comparing the indicator to a reference; and, b) providing an indicationof the results of the comparison to allow determination of a presence,absence or degree of venous insufficiency. 3) A method according toclaim 1, wherein the method includes, in a processing system: a)determining a first indicator value with the subject in a firstorientation; b) determining a second indicator value with the subject ina second orientation; and, c) determining an indicator change based on adifference between the first and second fluid indicator values, theindicator change being used in the assessment of venous insufficiency.4) A method according to claim 3, wherein the method includes, in theprocessing system: a) comparing the indicator change to a reference;and, b) providing an indication of the results of the comparison toallow determination of a presence, absence or degree of venousinsufficiency. 5) A method according to claim 1, wherein the methodincludes, in a processing system, determining an index using the atleast one impedance value, the index being indicative of a ratio ofextracellular to intracellular fluid levels in the at least leg segment,the index being used in the assessment of venous insufficiency. 6) Amethod according to claim 5, wherein the method includes, in theprocessing system: a) comparing the index to a reference; and, b)providing an indication of the results of the comparison to allowdetermination of a presence, absence or degree of venous insufficiency.7) A method according to claim 6, wherein the method includes,diagnosing the presence of venous insufficiency if: a) an indicator isless than first reference; and, b) an index is greater than a secondreference. 8) A method according to claim 5, wherein the methodincludes, in a processing system: a) determining a first index valuewith the subject in a first orientation; b) determining a second indexvalue with the subject in a second orientation; and, c) determining anindex change based on a difference between the first and second fluidindex values, the index change being used in the assessment of venousinsufficiency. 9) A method according to claim 1, wherein the methodincludes, in the processing system: a) determining a first indicatorvalue with the subject in a first orientation; b) after positioning thesubject in a second orientation for a predetermined time period,determining a second indicator value with the subject in the firstorientation; and, c) determining a difference between the first andsecond fluid indicator values, the difference being used in theassessment of venous insufficiency. 10) A method according to claim 9,wherein the method includes, in the processing system: a) monitoring thedifference; b) determining the time taken for the difference fall belowa reference; and, c) providing an indication of the time taken to allowdetermination of a presence, absence or degree of venous insufficiency.11) A method according to claim 1, wherein the method includes, in aprocessing system: a) determining a pre-treatment indicator value priorto treatment of the subject; b) determining a post-treatment indicatorvalue following treatment of the subject for venous insufficiency; and,c) determining an indicator change based on a difference between thepre-treatment and post-treatment indicator values, the indicator changebeing used in the assessment of venous insufficiency. 12) A methodaccording to claim 11, wherein the method includes, diagnosing thepresence of venous insufficiency if the indicator change is greater thana reference. 13) A method according to claim 1, wherein the methodincludes, in the processing system, using a reference that is at leastone of: a) an indicator or index determined for another limb of thesubject; b) a reference determined from a sample population; and, c) aprevious indicator or index determined for the subject. 14) A methodaccording to claim 1, wherein the method includes, in the processingsystem, displaying at least one of: a) an indicator; b) an index ratio;c) an index; d) an indicator change; e) an index change; f) one or moreimpedance parameter values; and, g) results of a comparison. 15) Amethod according to claim 1, wherein the at least one impedance value ismeasured at a measurement frequency of at least one of: a) less than 100kHz; b) less than 50 kHz; and, c) less than 10 kHz. 16) A methodaccording to claim 16, wherein the method includes, in the processingsystem, using the at least one impedance measurement as an estimate of aresistance of the subject at a zero measurement frequency. 17) A methodaccording to claim 1, wherein the method includes measuring at least onesecond impedance value, the at least one second impedance value beingmeasured at a measurement frequency of at least one of: a) greater than200 kHz; b) greater than 500 kHz; and, c) greater than 1000 kHz. 18) Amethod according to claim 16, wherein the method includes, in theprocessing system, using the at least one second impedance measurementas an estimate of a resistance of the subject at an infinite measurementfrequency. 19) A method according to claim 1, wherein the methodincludes, in the processing system: a) determining a plurality ofimpedance values; and, b) determining at least one impedance parametervalue from the plurality of impedance values. 20) A method according toclaim 19, wherein the impedance parameter values include at least oneof: R₀ which is the resistance at zero frequency; R_(∞) which is theresistance at infinite frequency; and, Z_(c) which is the resistance ata characteristic frequency. 21) A method according to claim 20, whereinthe method includes, in the processing system: a) determining values forimpedance parameters R₀ and R_(∞) from the measured impedance values;and, b) calculating the index (I) using the equation:$I = \frac{R_{\infty}}{R_{0} - R_{\infty}}$ 22) A method according toclaim 20, wherein the method includes, in the processing system,determining the parameter values using the equation:$Z = {R_{\infty} + \frac{R_{0} - R_{\infty}}{1 + \left( {{j\omega}\; \tau} \right)^{({1 - \alpha})}}}$where: Z is the measured impedance at angular frequency ω, τ is a timeconstant, and α has a value between 0 and
 1. 23) A method according toclaim 1, wherein the method includes, in the computer system, causingthe impedance measurements to be performed. 24) A method according toclaim 18, wherein the method includes, in the computer system: a)causing one or more electrical signals to be applied to the subjectusing a first set of electrodes; b) measuring electrical signals acrossa second set of electrodes applied to the subject in response to theapplied one or more signals; and, c) determining from the appliedsignals and the measured signals at least one measured impedance value.25) Apparatus for use in analysing impedance measurements performed on asubject, the apparatus including a processing system for: a) determiningat least one impedance value, indicative of the impedance of at leastleg segment of the subject; b) determining an indicator using the atleast one impedance value, the indicator being indicative ofextracellular fluid levels in the at least leg segment and being used inthe assessment of venous insufficiency. 26) Apparatus according to claim25, wherein the apparatus includes a processing system for: a) causingone or more electrical signals to be applied to the subject using afirst set of electrodes; b) measuring electrical signals across a secondset of electrodes applied to the subject in response to the applied oneor more signals; and, c) determining from the applied signals and themeasured signals at least one measured impedance value. 27) Apparatusaccording to claim 26, wherein the apparatus includes: a) a signalgenerator for generating electrical signals; and, b) a sensor forsensing electrical signals. 28) A method for use in assessing thepresence, absence or degree of venous insufficiency, the methodincluding, in a processing system: a) determining at least one impedancevalue, indicative of the impedance of at least one leg segment of thesubject; and, b) determining an indicator using the at least oneimpedance value, the indicator being indicative of extracellular fluidlevels in the at least leg segment and being used in the assessment ofvenous insufficiency. 29) A method for use in analysing impedancemeasurements performed on a subject, the method including, in aprocessing system: a) determining at least one impedance valueindicative of the impedance of at least one body segment of the subject;b) determining an indicator using at least one impedance value, theindicator being indicative of extracellular fluid levels in the at leastone body segment; c) determining an index using at least one impedancevalue, the index being indicative of a ratio of extracellular tointracellular fluid levels in the at least one body segment; d)comparing the indicator to a first reference; e) comparing the index toa second reference; and, f) providing an indication of the results ofthe comparisons. 30) A method according to claim 29, wherein the methodincludes, in the processing system, determining the indicator using animpedance measurement performed at a single low frequency. 31) A methodaccording to claim 29, wherein the at least one impedance measurement ismeasured at a measurement frequency of at least one of: a) less than 100kHz; b) less than 50 kHz; and, c) less than 10 kHz. 32) A methodaccording to claim 31, wherein the method includes, in the processingsystem, using the at least one impedance measurement as an estimate of aresistance of the subject at a zero measurement frequency. 33) A methodaccording to claim 29, wherein the method includes measuring at leastone second impedance value, the at least one second impedance valuebeing measured at a measurement frequency of at least one of: a) greaterthan 200 kHz; b) greater than 500 kHz; and, c) greater than 1000 kHz.34) A method according to claim 33, wherein the method includes, in theprocessing system, using the at least one second impedance measurementas an estimate of a resistance of the subject at an infinite measurementfrequency. 35) A method according to claim 29, wherein the methodincludes, in the processing system: a) determining at least twoimpedance values; and, b) determining at least one impedance parametervalue from the at least two impedance values. 36) A method according toclaim 35, wherein the method includes, in the processing system: a) ateach of three frequencies, determining first and second parameter valuesfor first and second impedance parameters relating to the impedance ofat least one body segment of the subject; b) solving simultaneousequations representing a circle defined with respect to the first andsecond impedance parameters to thereby determine circle parametervalues, the equations being solved using the first and second parametervalues at each of the three frequencies; c) using the circle parametervalues to determine a third impedance parameter value at a respectivefrequency; and, d) using the third impedance parameter value todetermine an indicator indicative of relative fluid levels within thebody segment of the subject. 37) A method according to claim 36, whereinthe first and second parameter values are resistance and reactancevalues. 38) A method according to claim 35, wherein the impedanceparameter values include at least one of: R₀ which is the resistance atzero frequency; R_(∞) which is the resistance at infinite frequency;and, Z_(c) which is the resistance at a characteristic frequency. 39) Amethod according to claim 38, wherein the method includes, in theprocessing system: a) determining values for impedance parameters R₀ andR_(∞) from the measured impedance values; and, b) calculating the index(I) using the equation: $I = \frac{R_{\infty}}{R_{0} - R_{\infty}}$ 40)A method according to claim 38, wherein the method includes, in theprocessing system, determining the parameter values using the equation:$Z = {R_{\infty} + \frac{R_{0} - R_{\infty}}{1 + \left( {{j\omega}\; \tau} \right)^{({1 - \alpha})}}}$where: Z is the measured impedance at angular frequency ω, τ is a timeconstant, and α has a value between 0 and
 1. 41) Apparatus for use inanalysing impedance measurements performed on a subject, the apparatusincluding a processing system for: a) determining at least one impedancevalue indicative of the impedance of at least one body segment of thesubject; b) determining an indicator using at least one impedance value,the indicator being indicative of extracellular fluid levels in the atleast one body segment; c) determining an index using at least oneimpedance value, the index being indicative of a ratio of extracellularto intracellular fluid levels in the at least one body segment; d)comparing the indicator to a first reference; e) comparing the index toa second reference; and, f) providing an indication of the results ofthe comparisons. 42) Apparatus according to claim 41, wherein theprocessing system is for: a) causing one or more electrical signals tobe applied to the subject using a first set of electrodes; b) measuringelectrical signals across a second set of electrodes applied to thesubject in response to the applied one or more signals; and, c)determining from the applied signals and the measured signals at leastone measured impedance value. 43) Apparatus according to claim 41,wherein the apparatus includes: a) a signal generator for generatingelectrical signals; and, b) a sensor for sensing electrical signals. 44)A method for use in distinguishing the presence of oedema andlymphoedema in a subject, the method including, in a processing system:a) determining at least one impedance value indicative of the impedanceof at least one body segment of the subject; b) determining an indicatorusing at least one impedance value, the indicator being indicative ofextracellular fluid levels in the at least one body segment; c)determining an index using at least one impedance value, the index beingindicative of a ratio of extracellular to intracellular fluid levels inthe at least one body segment; d) comparing the indicator to a firstreference; e) comparing the index to a second reference; and, f)providing an indication of the results of the comparisons, the resultsbeing used to distinguish oedema and lymphoedema.